The Metabolic Core and Catalytic Switches Are Fundamental Elements in the Self-Regulation of the Systemic Metabolic Structure of Cells

[Background] Experimental observations and numerical studies with dissipative metabolic networks have shown that cellular enzymatic activity self-organizes spontaneously leading to the emergence of a metabolic core formed by a set of enzymatic reactions which are always active under all environmental conditions, while the rest of catalytic processes are only intermittently active. The reactions of the metabolic core are essential for biomass formation and to assure optimal metabolic performance. The on-off catalytic reactions and the metabolic core are essential elements of a Systemic Metabolic Structure which seems to be a key feature common to all cellular organisms. [Methodology/Principal Findings] In order to investigate the functional importance of the metabolic core we have studied different catalytic patterns of a dissipative metabolic network under different external conditions. The emerging biochemical data have been analysed using information-based dynamic tools, such as Pearson's correlation and Transfer Entropy (which measures effective functionality). Our results show that a functional structure of effective connectivity emerges which is dynamical and characterized by significant variations of bio-molecular information flows. [Conclusions/Significance] We have quantified essential aspects of the metabolic core functionality. The always active enzymatic reactions form a hub –with a high degree of effective connectivity- exhibiting a wide range of functional information values being able to act either as a source or as a sink of bio-molecular causal interactions. Likewise, we have found that the metabolic core is an essential part of an emergent functional structure characterized by catalytic modules and metabolic switches which allow critical transitions in enzymatic activity. Both, the metabolic core and the catalytic switches in which also intermittently-active enzymes are involved seem to be fundamental elements in the self-regulation of the Systemic Metabolic Structure.Consejo Superior de Investigaciones Cientificas (CSIC),grant 201020I026. Ministerio de Ciencia e Innovacion (MICINN). Programa Ramon y Cajal. Campus de Excelencia Internacional CEI BioTIC GENIL, grant PYR-2010-14. Junta de Andalucia, grant P09-FQM-4682

Cognitive Reserve Characteristics and Occupational Performance Implications in People with Mild Cognitive Impairment

The Cognitive Reserve hypothesis suggests that there are individual differences in the ability to cope with the pathologic changes in Alzheimer’s Disease. The proportion of elderly individuals has increased in recent years; this increase emphasizes the importance of early detection of mild cognitive impairment and the promotion of healthy ageing. The purpose of our study is to characterize cognitive reserve and occupational performance implications in people with mild cognitive impairment. 125 patients with mild cognitive impairment were enrolled. The Montreal Cognitive Assessments (MoCA) was used to evaluate cognitive status and the Cognitive Reserve Index Questionnaire (CRIq) as an indicator of cognitive reserve. Higher level of education was associated with higher MoCA scores (r = 0.290, p = 0.001). Positive significant correlations were observed between MoCA and total CRIq (r = 0.385, p < 0.001) as well as its three sub-domains, education (r = 0.231, p = 0.010), working activity (r = 0.237, p = 0.008) and leisure time (r = 0.319, p < 0.001). This study findings provide the importance of considering socio-behavioral factors in cognitive status. This research helps to describe the importance of engaging occupationally along the whole life-course as a potential protective factor in ageing, and includes a perspective of occupational therapy regarding the hypothesis of cognitive reserve.Depto. de EnfermeríaFac. de Enfermería, Fisioterapia y PodologíaTRUEpu

Precursors of fatty alcohols in the ISM: Discovery of n-propanol

Theories on the origins of life propose that early cell membranes were synthesized from amphiphilic molecules simpler than phospholipids such as fatty alcohols. The discovery in the interstellar medium (ISM) of ethanolamine, the simplest phospholipid head group, raises the question whether simple amphiphilic molecules are also synthesized in space. We investigate whether precursors of fatty alcohols are present in the ISM. For this, we have carried out a spectral survey at 7, 3, 2 and 1 mm toward the Giant Molecular Cloud G+0.693-0.027 located in the Galactic Center using the IRAM 30m and Yebes 40m telescopes. Here, we report the detection in the ISM of the primary alcohol n-propanol (in both conformers Ga-n-C3H7OH and Aa-n-C3H7OH), a precursor of fatty alcohols. The derived column densities of n-propanol are (5.5+-0.4)x10^13 cm^-2 for the Ga conformer and (3.4+-0.3)x10^13 cm^-2 for the Aa conformer, which imply molecular abundances of (4.1+-0.3)x10^-10 for Ga-n-C3H7OH and of (2.5+-0.2)x10^-10 for Aa-n-C3H7OH. We also searched for the AGa conformer of n-butanol (AGa-n-C4H9OH) without success yielding an upper limit to its abundance of <4.1x10^-11. The inferred CH3OH:C2H5OH:C3H7OH:C4H9OH abundance ratios go as 1:0.04:0.006:<0.0004 toward G+0.693-0.027, i.e. they decrease roughly by one order of magnitude for increasing complexity. We also report the detection of both syn and anti conformers of vinyl alcohol, with column densities of (1.11+-0.08)x10^14 cm^-2 and (1.3+-0.4)x10^13 cm^-2, and abundances of (8.2+-0.6)x10^-10 and (9.6+-3.0)x10^-11, respectively. The detection of n-propanol, together with the recent discovery of ethanolamine in the ISM, opens the possibility that precursors of lipids according to theories of the origin of life, could have been brought to Earth from outer space.Comment: 15 pages, 10 figures, accepted for A&

Priority questions in multidisciplinary drought research

Addressing timely and relevant questions across a multitude of spatio-temporal scales, state-of-the-art interdisciplinary drought research will likely increase in importance under projected climate change. Given the complexity of the various direct and indirect causes and consequences of a drier world, scientific tasks need to be coordinated efficiently. Drought-related research endeavors ranging from individual projects to global initiatives therefore require prioritization. Here, we present 60 priority questions for optimizing future drought research. This topical catalogue reflects the experience of 65 scholars from 21 countries and almost 20 fields of research in both natural sciences and the humanities. The set of drought-related questions primarily covers drought monitoring, impacts, forecasting, climatology, adaptation, as well as planning and policy. The questions highlight the increasingly important role of remote sensing techniques in drought monitoring, importance of drought forecasting and understanding the relationships between drought parameters and drought impacts, but also challenges of drought adaptation and preparedness policies

Coffee consumption and gastric cancer: a pooled analysis from the Stomach cancer Pooling Project consortium

Objective: This study aimed to evaluate and quantify the relationship between coffee and gastric cancer using a uniquely large dataset from an international consortium of observational studies on gastric cancer, including data from 18 studies, for a total of 8198 cases and 21 419 controls. Methods: A two-stage approach was used to obtain the pooled odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) for coffee drinkers versus never or rare drinkers. A one-stage logistic mixed-effects model with a random intercept for each study was used to estimate the dose-response relationship. Estimates were adjusted for sex, age and the main recognized risk factors for gastric cancer. Results: Compared to never or rare coffee drinkers, the estimated pooled OR for coffee drinkers was 1.03 (95% CI, 0.94-1.13). When the amount of coffee intake was considered, the pooled ORs were 0.91 (95% CI, 0.81-1.03) for drinkers of 1-2 cups per day, 0.95 (95% CI, 0.82-1.10) for 3-4 cups, and 0.95 (95% CI, 0.79-1.15) for five or more cups. An OR of 1.20 (95% CI, 0.91-1.58) was found for heavy coffee drinkers (seven or more cups of caffeinated coffee per day). A positive association emerged for high coffee intake (five or more cups per day) for gastric cardia cancer only. Conclusions: These findings better quantify the previously available evidence of the absence of a relevant association between coffee consumption and gastric cancer

Association of Candidate Gene Polymorphisms With Chronic Kidney Disease: Results of a Case-Control Analysis in the Nefrona Cohort

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2, 445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionizationtime of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD

Combined Point-of-Care Nucleic Acid and Antibody Testing for SARS-CoV-2 following Emergence of D614G Spike Variant

Rapid COVID-19 diagnosis in the hospital is essential, although this is complicated by 30%–50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant dominates the pandemic and it is unclear how serological tests designed to detect anti-spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild-type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95% CI 57.8–92.9) by rapid NAAT alone. The combined point of care antibody test and rapid NAAT is not affected by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity

The ATLAS fast tracKer system

The ATLAS Fast TracKer (FTK) was designed to provide full tracking for the ATLAS high-level trigger by using pattern recognition based on Associative Memory (AM) chips and fitting in high-speed field programmable gate arrays. The tracks found by the FTK are based on inputs from all modules of the pixel and silicon microstrip trackers. The as-built FTK system and components are described, as is the online software used to control them while running in the ATLAS data acquisition system. Also described is the simulation of the FTK hardware and the optimization of the AM pattern banks. An optimization for long-lived particles with large impact parameter values is included. A test of the FTK system with the data playback facility that allowed the FTK to be commissioned during the shutdown between Run 2 and Run 3 of the LHC is reported. The resulting tracks from part of the FTK system covering a limited η-ϕ region of the detector are compared with the output from the FTK simulation. It is shown that FTK performance is in good agreement with the simulation. © The ATLAS collaboratio

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Novel Common Genetic Susceptibility Loci for Colorectal Cancer

BACKGROUND: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. METHODS: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. RESULTS: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. CONCLUSIONS: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screenin